High-throughput screening (HTS) of libraries with large numbers of small molecules is a widely recognized and increasingly used method for identifying compounds that modulate biological processes. Compounds thus identified can be powerful molecular probes for dissecting complex biological pathways, and may also be potential leads for clinical use. In the context of biodefense and emerging infectious disease, small molecule HTS could lead to the discovery of new classes of antimicrobial agents or novel stimulators of innate or adaptive immunity, and also identify and validate novel targets for subsequent drug discovery efforts. The National Small Molecule Screening Laboratory for the RCEs in Biodefense and Emerging Infectious Disease (NSRB) was established in 2003 to provide access to small molecule high-throughput screening (HTS) and medicinal chemistry resources for all U.S. investigators conducting research on NIAID Priority Pathogens. It has been a highly successful program and several NSRB projects have produced reagents that are progressing toward possible therapeutic development. The NERCE National Small Molecule Screening and Medicinal Chemistry Core (Core C) propsed here is a continuation of the NSRB. The main goals for Core C are to: Provide access to small-molecule HTS for all U.S. investigators with projects focused on NIAID Priority Pathogens and agents of Emerging Infectious Diseases, and to Provide data analysis and medicinal chemistry resources for maturation of screening positives into smallmolecule research tools or into potential novel therapeutic leads.